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Title:VE-cadherin mechanotransduction signaling and its regulation by extracellular matrix
Author(s):Kong, Xinyu
Director of Research:Leckband, Deborah E
Doctoral Committee Chair(s):Leckband, Deborah E
Doctoral Committee Member(s):Fratti, Rutilio A; Brieher, William M; Zhang, Kai
Department / Program:Biochemistry
Discipline:Biochemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):VE-cadherin
Cell signaling
Mechanotransduction
Extracellular matrix
Rigidity sensing
Endothelial permeability
Abstract:This thesis focuses on signaling pathways that regulate the integrity of inter endothelial junctions in response to mechanical perturbations. The vascular endothelium forms a natural barrier between blood and tissues and its disruption leads to blood leakage and serious pathological consequences. VE-cadherin—the primary adhesion molecule at cell-cell junctions in vascular endothelial cells—governs the barrier integrity of the vascular endothelium. Previous studies showed that increased tension on VE-cadherin triggers a mechanotransduction response that affects endothelial permeability. In this dissertation, I focus on VE-cadherin force-activated signaling cascades that mediate endothelial permeability. At the same time, cadherin-based mechanotransduction also triggers the recruitment of vinculin and actin to cadherin complexes, to reinforce intercellular adhesions. Studies in this thesis investigated the underlying signaling pathways and the impact of the extracellular matrix environment on both barrier protective and barrier disruptive responses. Studies described in Chapter 2 indicate that VE-cadherin triggers a global signaling cascade that involves VEGFR2, PI3K, Integrins, FAK and RhoA GTPase. The signaling also leads to vinculin and actin recruitment downstream of integrin activation, which is a potential mechanism to protect the cell-cell junctions against disruption. Chapter 3 investigates how extracellular matrix (ECM) proteins and rigidity regulate the force-induced signaling pathway. In pathological situations like pulmonary fibrosis, the change of ECM can affect the endothelium permeability in response to mechanical perturbations. In this chapter, I showed that ECM proteins and the substrate rigidity coordinate to modulate force activated signaling cascades. Findings show the ECM-dependent regulation of endothelial permeability, in response to mechanical perturbations. This finding provides a potential mechanism through which the ECM may regulates the endothelial integrity in a dynamic mechanical environment. The impact of the ECM on endothelial permeability is further examined at the tissue-level, using a cyclic stretch device, as presented in Chapter 4. Using a home-built cyclic stretching device, physiological levels of equibiaxial cyclic stretch (CS) are applied to mimic mechanical stimulation during respiration. Stretch-induced vinculin recruitment is regulated by ECM proteins and matrix rigidity, similar to the results with VE-cadherin-specific perturbations in Chapter 3. Studies further showed that CS-induced increases in endothelial monolayer permeability depend on the ECM composition and matrix rigidity. These findings provide insights into how the composition and rigidity of the ECM coordinate with intercellular mechanotransduction to regulate endothelial permeability. This work contributes our understanding of the mechanical environment that can exacerbate vascular diseases such as lung fibrosis, ventilator induced lung injury, or atherosclerosis. It could also guide the development of biomaterials for tissue engineering.
Issue Date:2020-07-13
Type:Thesis
URI:http://hdl.handle.net/2142/108590
Rights Information:Copyright 2020 Xinyu Kong
Date Available in IDEALS:2020-10-07
Date Deposited:2020-08


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